CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 16, 2023
Expiration: August 15, 2024
mCRPC Case Study 1: A Patient With Newly Diagnosed mCRPC and No Previous ARSI Therapy, No BRCA Mutation
Alicia K. Morgans, MD, MPH:
We are going to discuss a few different scenarios based on a single case study of mCRPC. A 65-year-old patient with a PSA of 380, Gleason 5+3, and bone metastases. The patient had both germline and somatic testing, which came back BRCA wild type. This patient had mHSPC and received ADT plus docetaxel at a time when that was a recommended choice.
Now he has first line mCRPC and wants to be aggressive with his therapy. What will you do and why?
mCRPC: Background
Rana R. McKay, MD:
The treatment options for mCRPC are expanding, and it is great to see that there are multiple agents available with unique mechanisms of action, from hormonally driven therapies to chemotherapy, radioligand therapy, targeted therapy with PARP inhibitors, and immunotherapy. There is now a spectrum of approved agents in the mCRPC setting, which is quite exciting.3
Expert Insight Into Management of First-line mCRPC
Rana R. McKay, MD:
Even though we may periodically see individuals who had docetaxel for mHSPC, I want to highlight that in the modern era, there is no role for docetaxel monotherapy in the mHSPC setting. If you use docetaxel, it should be coupled with an AR targeting agent or just use an AR-targeting agent.
This patient is coming into mCRPC not having seen an ARSI, and the hope is that this becomes an ever decreasing patient population. I think it makes perfect sense to consider doing an ARSI first for a patient who has never received one before. This could be abiraterone (approved based on the phase III COU-AA-30128 and COU-AA-30229 trials) or enzalutamide (approved based on the phase III PREVAIL30 and AFFIRM31 trials), both of which are strongly planted in the mCRPC setting.
David VanderWeele, MD, PhD:
Abiraterone would be the most likely therapy for this patient, although I think enzalutamide is an acceptable option. I might bring up the use of sipuleucel-T. I probably would not discuss radium-223 at this point, but in certain circumstances it is possible.
Michael T. Schweizer, MD:
I like abiraterone in this setting too. I think it strikes a good balance of tolerability and efficacy.
Importance of Genetic and Tumor Testing
Tanya B. Dorff, MD:
Of importance, this patient did have next-generation sequencing, which is very important in the setting of mCRPC now with the approval of 2 AR inhibitor plus PARP inhibitor combinations for various homologous recombination repair (HRR) gene alterations. Because this patient is BRCA wild type and presumably without another HRR alteration, currently there is no approved PARP inhibitor combination for him.
mCRPC Case Study 2: A Patient With Newly Diagnosed mCRPC and Previous ARSI Therapy, No BRCA Mutation
Alicia K. Morgans, MD, MPH:
If the patient were BRCA wild type but had received previous ARSI therapy, what would you do?
Tanya B. Dorff, MD:
In a patient post ARSI who does not have an HRR alteration, we typically consider chemotherapy, but there are some other options. Sipuleucel-T was studied before abiraterone and enzalutamide existed, so we could argue there are not data for its use after abiraterone or enzalutamide.32 However, for a patient with slowly progressing first line mCRPC, I still think sipuleucel-T is reasonable if they are asymptomatic or minimally symptomatic.
For symptomatic patients, radium-223 has palliative benefits as well as a survival advantage, although in the phase III ALSYMPCA trial 57% of the patients had received docetaxel previously and 43% had not.33 For patients with bone predominant disease who are not eligible for docetaxel or prefer to delay it, radium-223 is another option. But for now, we typically rely heavily on chemotherapy in this scenario.
Alicia K. Morgans, MD, MPH:
I would also add that if a patient were on ADT plus ARSI in mHSPC, I would not put them on an ARSI again in first-line mCRPC. I feel pretty strongly about changing mechanism of action in that situation.
Michael T. Schweizer, MD:
In practice, we all know there are high rates of cross-resistance between abiraterone and enzalutamide, for example. However, I see a lot of patients who have been on abiraterone for years, and then their PSA starts to slowly drift up. If staging scans just show subtle growth in nodes and they remain asymptomatic, I will often try enzalutamide. If it does not work we can always switch therapy after a couple months. Overall, I expect 1 in 5 patients to respond to enzalutamide after abiraterone, which means delaying chemotherapy for these patients. So, I do not completely discount using an ARSI in that scenario; it may not be the most active regimen, but I also feel like it might be overkill to reflexively put everyone on chemotherapy at that point.
Alicia K. Morgans, MD, MPH:
In that patient you talked about, I most commonly do not use chemotherapy next. Sometimes I will switch them to enzalutamide and give them sipuleucel-T. I consider it an asymptomatic window, so I put them on that therapy and sometimes we see a response.
David VanderWeele, MD, PhD:
I have also seen more activity using enzalutamide after abiraterone than vice versa. I have a hard time coming up with an example in my mind of someone who got clear benefit from switching ARSI to abiraterone.
Incorporating Lu-177-PSMA-617
Alicia K. Morgans, MD, MPH:
Taking this case to the next step, after chemotherapy, when do you consider using Lu-177-PSMA-617?
Rana R. McKay, MD:
I am currently using it in the post-ARSI, post-taxane space. Lu-177-PSMA-617 is approved for adult patients with PSMA-positive mCRPC who have been treated with ARSI and taxane-based chemotherapy.34 On the study, patients were identified as PSMA positive using 68Ga-PSMA-11 imaging and the reference standard defined in the phase III VISION trial of uptake above the background of liver and a lack of non–PSMA positive soft tissue disease.27 In clinical practice, other PSMA PET imaging tools can be used for the detection of PSMA PET–positive disease.
David VanderWeele, MD, PhD:
I am following the label. Our nuclear medicine department is strict about using Lu-177-PSMA-617 post- docetaxel and, basically, we cannot prescribe it outside of those parameters. We are enrolling on another phase III trial with a different PSMA radioligand for the chemotherapy-naive CRPC setting (NCT05204927).
Alicia K. Morgans, MD, MPH:
We also use Lu-177-PSMA-617 on label, except on clinical trial.
Lu-177-PSMA-617 Usage in Chemotherapy-Naive mCRPC
Michael T. Schweizer, MD:
We mostly use Lu-177-PSMA-617 per the label, post docetaxel. There are a few cases where we will prescribe it prechemotherapy if a patient is a poor candidate for chemotherapy.
Rana R. McKay, MD:
I agree. One of the big questions I think we struggle with in the clinic is what to do with somebody who is not fit for chemotherapy. Are you going to deny them access to Lu-177-PSMA-617? There is an access issue currently, with people who are waiting to get treatment, so we are trying to treat people per the label. However, I think this is going to become an increasing dilemma as the Lu-177-PSMA-617 becomes more readily available and the PSMAfore data are presented.
Tanya B. Dorff, MD:
We also would not typically use Lu-177-PSMA-617 in a patient like the one described. As Dr. McKay noted, the data from PSMAfore might change that. The phase III PSMAfore trial (NCT04689828) is exploring Lu-177-PSMA-617 vs switching androgen therapy in this patient population. A recent press release indicated that this trial met its primary endpoint of improved rPFS. We await the presentation of these data, but if the data are strongly positive for radiopharmaceutical use ahead of docetaxel, it might open the door to treatment of these patients.
Rana R. McKay, MD:
We will want to see how striking the benefit of Lu-177-PSMA-617 is. What do the secondary endpoints look like, and even though the study may not be powered for OS, what does the OS signal look like? I think this is going to be really important as this agent potentially moves up in the treatment landscape.
Ongoing Phase III Trials of PSMA-targeting Radionuclides
Tanya B. Dorff, MD:
There are other radiopharmaceuticals in development, many of which target PSMA but look to improve on the kinetics of dwell of radioactivity in the tumor. Some use an antibody vs the Lu-177-PSMA-617 that is currently approved, or an alpha-particle radiation instead of a beta particle. For a patient where Lu-177-PSMA-617 would be off label, we would ideally be enrolling them on one of those clinical trials, and there are quite a few of them out there, fortunately.
Choosing Between Cabazitaxel and Lu-177-PSMA-617
Alicia K. Morgans, MD, MPH:
For a patient who has already received an ARSI and docetaxel, how do you choose between Lu-177-PSMA-617 and cabazitaxel?
Tanya B. Dorff, MD:
I think we are really looking to get more data about using PSMA PET to optimally select which therapy to go to first. The phase II TheraP trial was a head-to-head comparison of Lu-177-PSMA-617 vs cabazitaxel in patients with PSMA-positive mCRPC (N = 200).35,36 This was not a survival trial; rather, it used PSA response rate (proportion of patients with a PSA reduction ≥50% from baseline) as the primary endpoint. The OS was similar between the arms, but PFS and PSA responses were greater with Lu-177-PSMA-617 compared with cabazitaxel in the intention-to-treat population. This trial had a relatively high bar of PSMA positivity for enrollment, which may have contributed to seeing the higher response rates. Ideally, patients will receive both cabazitaxel and Lu-177-PSMA-617 because we want to use all available life prolonging therapies, but someone with a less avid PSMA PET scan may potentially do better with cabazitaxel.
David VanderWeele, MD, PhD:
I often prioritize Lu-177-PSMA-617 over cabazitaxel, and I ask our radiologists for additional information about standardized uptake value (SUV) metrics if I am in doubt. Lu-177-PSMA-617 is currently hard to obtain, so you want to offer it to a patient if you have a slot available. I might do cabazitaxel or cabazitaxel plus carboplatin instead of Lu-177-PSMA-617 if a patient’s disease seems to be progressing really quickly.
Michael T. Schweizer, MD:
SUV parameters are something we look at when deciding between Lu-177-PSMA-617 and cabazitaxel. Data from our clinic as well as the VISION trial show that patients do not do that well if the SUV mean is <10.27 If I have a patient where most of their lesions look less avid, I will probably consider cabazitaxel first. We also routinely obtain PSMA PET and FDG PET scans at baseline for all our patients. If I see someone who is FDG avid with moderate to low PSMA avidity, I worry a lot more about an aggressive variant and, in that context, would tend to favor cabazitaxel and potentially adding carboplatin.
mCRPC Case Study 3: A Patient With Newly Diagnosed BRCA-Mutant mCRPC
Alicia K. Morgans, MD, MPH:
Taking this same case study, what if the patient had a BRCA mutation and had only received docetaxel previously? Would the conversation be different?
Let me set the stage by describing the studies that led to the recent approvals of PARP/ARSI combinations for selected patients with mCRPC. The phase III PROpel study evaluated olaparib plus abiraterone vs abiraterone as first-line therapy for patients with mCRPC. The addition of a PARP inhibitor significantly prolonged imaging-based PFS in the intent-to-treat population (primary endpoint) compared with placebo plus abiraterone (24.8 vs 16.6 months; HR: 0.66; 95% CI: 0.54-0.81; P <.001).37 The subgroup of patients with HRR mutations showed greater improvement in rPFS (HR: 0.5; 95% CI: 0.34-0.73) with the combination vs abiraterone/prednisone alone. The FDA approved olaparib plus abiraterone/prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated mCRPC.38
Similarly, the phase III TALAPRO 2 trial examined first-line talazoparib plus enzalutamide vs enzalutamide in patients with mCRPC and HRR mutations. The study demonstrated significant improvement in median rPFS for talazoparib plus enzalutamide in the intention-to-treat population vs placebo plus enzalutamide (not reached vs 21.9 months; HR: 0.63; 95% CI: 0.51-0.78; P <.001).39 HRR mutations examined in the trial were BRCA1/2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, and CDK12. The rPFS for patients with an HRR mutation receiving talazoparib plus enzalutamide was not reached vs 13.8 months for patients with an HRR mutation receiving enzalutamide (HR: 0.45; 95% CI: 0.33-0.61; P <.0001). The FDA recently approved the combination of talazoparib with enzalutamide for HRR gene–mutated mCRPC.40
Tanya B. Dorff, MD:
With a BRCA mutation and no previous ARSI, the patient could be offered either olaparib plus abiraterone/prednisone or talazoparib plus enzalutamide. However, most patients will have received either abiraterone or enzalutamide before this stage, which makes the PROpel and TALAPRO 2 studies harder to apply.
Michael T. Schweizer, MD:
I am still a bit skeptical whether using a combination PARP inhibitor plus AR inhibitor even makes sense for patients with BRCA mutations vs single-agent PARP inhibition. We know from other trials (eg, TRITON3, PROFOUND)41,42 that when you use PARP inhibitors in patients with BRCA altered disease, outcomes are better compared with AR inhibitors or docetaxel. TALAPRO-2 and PROpel did not compare combination PARP inhibitor plus AR inhibitor with PARP inhibitor treatment alone, so it is possible that the added AR inhibitor adds to toxicity without really improving overall outcomes in the BRCA altered patient population. I think there are actually more questions than answers from these studies.
The other concern I have with the PARP inhibitor/ARSI combination trials is that they mostly enrolled patients who had not received treatment intensification in the hormone sensitive setting. Thus, we do not know whether a patient who has developed resistance to one of the more aggressive therapeutic regimens is still going to benefit from a PARP inhibitor/ARSI combination. I do not think we can just assume that giving the combination will be more effective in that context.
There was considerable toxicity in the PROpel study. Rates of anemia are quite high with the combination (any grade: 46.0% vs 16.4%; grade ≥3: 15.1% vs 3.3%) compared with placebo plus abiraterone. I struggle with recommending a more toxic therapy without any clear cut evidence that it is going to extend life or improve quality of life, which to me is still up for debate.
Rana R. McKay, MD:
I would switch to a PARP inhibitor. Olaparib is indicated in the chemotherapy-naive setting for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene–mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.38 In the randomized phase III TRITON3 study, patients with deleterious BRCA-mutated mCRPC who had progressed on a previous second-generation AR inhibitor had a significantly longer median imaging-based PFS after rucaparib treatment (11.2 vs 6.4 months; HR: 0.50; 95% CI: 0.36-0.69; P <.001) compared with the physician’s choice control arm (docetaxel or AR inhibitor [abiraterone or enzalutamide]).41 In this study, using rucaparib before docetaxel was actually a better strategy than jumping to docetaxel for patients with a BRCA1/2 alteration. I think there are data to support PARP inhibitors in the chemotherapy-naive setting for patients with HRR mutations, specifically those with BRCA1/2 alterations.
For a patient with previous ARSI therapy, there are no data for layering in a PARP inhibitor in this context and, quite honestly, in most scenarios where we have continued the ARSI and layered in the alternate agent, it has failed. When we did that with abiraterone and enzalutamide, it failed.43 When we did it with docetaxel and enzalutamide, it failed. We have demonstrated from multiple studies that sequential ARSIs, whether by layering or adding them in after exposure, have not really been beneficial and can be associated with increased toxicity.44
Alicia K. Morgans, MD, MPH:
Caution and questions remain regarding whether the combination is necessary vs a sequencing approach for PARP inhibitors and ARSI. The combination is potentially an option if you want to be more intensive and more aggressive against the disease while recognizing the compromises in quality of life, and we are really considering it in patients with BRCA1/2 mutations rather than a larger population.
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